1,2-oxazine derivatives in alleviating pain and treating inflammatory diseases

ABSTRACT

THE COMPOUNDS ARE OFTHECLASS OF (P-(3,6-DIHYDRO-2H1,2-OXAZIN-2-YL)-PHENYL)-ALKANOIC ACIDS, THE METHYL AND ETHYL ESTERS THEREOF, AS WELL AS THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF AND HAVE ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY, THE COMPOUNDS ARE ACTIVE INGREDIENTS OF PHARMACEUTICAL COMPOSITIONS AND ARE USEFUL FOR ALLEVIATING PAIN ANDTREATING INFLAMMATORY DISEASES IN MAMMALS, AN ILLUSTRATIVE EMBODIMENT IS (P-(3,6-DIHYDRO-2H1,2-OXAZIN-2-YL)-PHENYL)-ACETIC ACID.

United States Patent 3,729,559 1,2-0XAZINE DERIVATIVES IN ALLEVIATINGPAIN AND TREATING INFLAMMATORY DISEASES Rolf Denss, Basel, Switzerland,Niels Clauson-Kaas,

Farum, Denmark, and Franz Ostermayer, Riehen, Switlzerglgand, assignorsto Ciba-Geigy Corporation, Ardsley,

No Drawing. Original application Apr. 22, 1969, Ser. No. 818,407, nowPatent No. 3,586,676, dated June 22, 1971. Divided and this applicationJan. 8, .1971, Ser.

Int. Cl. A61k 27/00 US. Cl. 424-248 3 Claims ABSTRACT OF THE DISCLOSURECROSS-REFERENCE TO RELATED APPLICATION This is a divisional of Ser. No.818,407, filed Apr. 22, 1969, now US. Pat. No. 3,586,676.

DETAILED DESCRIPTION The present invention concerns 1,2-oxazinyl phenylalkanoic acid derivatives, pharmaceutical compositions comprising thesecompounds and a pharmaceutical carrier and methods of alleviating painand treating inflammatory diseases in mammals comprising administeringthem.

More particularly, the present invention concerns compounds of theformula O I R1 R2 (1) wherein R is hydrogen, methyl or ethyl,

R is hydrogen or halogen up to the atomic number 35,

and

R is hydrogen, methyl or ethyl,

and the pharmaceutically acceptable salts of the compounds of Formula I,wherein R is hydrogen.

In the compounds of Formula I and the starting materials mentionedbelow, R as halogen up to the atomic number 35, can be fiuoro, chloro orbromo.

Compounds of Formula .I, wherein R is methyl or ethyl have an opticallyactive carbon atom giving rise to enantiomeric forms. Embraced by thepresent invention are the racemates as well as the single enantiomers.

A preferred subclass are the compounds of Formula I wherein R ishydrogen or methyl, R is hydrogen or chloro and R is hydrogen, and thepharmaceutically acceptable salts thereof.

Preferred members of the compounds of Formula I are [p-(3,6 dihydro 2H1,2 oxazin 2 yl)-phenyl1- acetic acid, 2 [3 chloro 4 (3,6 dihydro2H-1,2- oxazin-Z-yl)-phenyl]-propi0nic acid and the pharmaceuticallyacceptable salts thereof.

The compounds of the present invention were found to have valuablepharmacological properties, in particu- 3,729,559 Patented Apr. 24, 1973lar analgesic, anti-inflammatory and anti-pyretic activity, combinedwith a favorable therapeutic index. The pharmacological activity of thecompounds of the invention is determined in various standard tests withexperimental animals.

The analgesic activity is demonstrated in the writhing test in mice.This test is described by E. Siegmund, R. Cadmus and G. Lu, Proc. Soc.Exp. Biol. Med. 95, 729 (1957). The amount of test substance isdetermined preventing the test animals the syndrome produced byintraperitoneal injection of 2-phenyl-1,4-benzoquinone. Excellentresults are obtained by oral administration of 10 mg./kg. of bodyweightof 2-[3-chloro-4-(3,6-dihydro-2H- 1,2-oxazin-2-yl -phenyl] -propionicacid.

As an example of the use as anti-inflammatory agent, the use of 2 [3chloro 4 (3,6 dihydro 2H-l,2- oxazin 2 yl) phenyl]-propionic acid inbolus alba induced edema in the rat paw is described. The test used isthat described by G. Wilhelmi, lap. Journ. Pharmac. 15, 190 (1965). Thecompound under investigation is administered to rats perorally throughan esophageal sound. One hour thereafter, bolus alba edema is induced bysubcutaneous injection of 0.1 ml. of a 10% suspension of finely sievedbolus alba in tragacanth into the plantar region of the right hand pawof the rats. Another group of rats having not obtained the testcompound, but the bolus alba, serves as control group. Each groupconsists of 20 male albino rats weighing about to about g. The intensityof the swelling of the rats paw is determined 5 hours after the bolusalba injection, by measuring the weight differences of the unswollenleft paws and the swollen right paws. Thus it is determined that2-[3-chloro 4 (3,6 dihydro 2H 1,2 oxazin 2 yl)-phenyl] propionic acidadministered in a dosage of about 25 mg./ kg. of bodyweightsignificantly inhibits the formation of the bolus alba edema indicatinga pronounced anti-inflammatory activity.

Similar analgesic and anti-inflammatory activitties are found with othercompounds of the invention.

The toxicity of the compounds of the invention on oral administration isof favorable low order.

The new 1,2-oxazinylphenylalkanoic acids and esters of Formula I andtheir pharmaceutically acceptable salts with inorganic and organic basesare suitable as active ingredients for pharmaceutical compositions,which can be administered orally, rectally or parenterally, for therelief and removal of pains of varying origin and for the treatment ofrheumatic and other inflammatory diseases.

Compounds of Formula I are produced by reacting a compound of Formula IIwith butadiene and hydrolysing the reaction product of Formula Iawherein R R and R have the meanings given under Formulae I and II to thecorresponding acid and con verting, if desired, the acid so obtainedinto a salt with an inorganic or organic base.

The reaction of the nitroso compound of Formula II with butadiene isperformed, for example, at temperatures between and 80 in an Organicsolvent such as chloroform, benzene or acetic acid, or in an excess ofbutadiene if necessary in a closed vessel. The optionally subsequenthydrolysis is carried out in the usual manner, e.g. by reacting theobtained compound of Formula Ia with an alkanolic aqueous alkalisolution such as ethanolic sodium hydroxide solution preferably at roomtemperature.

The Z-(p-nitrosophenyl)-alkanoic acid alkyl esters of Formula II whichare used as starting materials for the reaction sequence according tothe invention, are new compounds. They are produced, for example, by thereduction of corresponding p-nitro compounds, e.g. by means of zinc dustin ethanol, to give p-hydroxyamino compounds, and partial reoxidation ofthe latter e.g. by means of iron('III)-chloride in aqueous-ethanolicsolution.

Optionally produceable pharmaceutically acceptable salts of the acidsfalling under Formula I are dervied from inorganic and organic bases viaconventional methods. Such salts include, for example the sodium,potassium, lithium, magnesium, calcium and ammonium salts, as well assalts derived from ethylamine, triethylarnine, 2- aminoethanol, 2,2iminodiethanol, 2 dimethylaminoethanol, Z-diethylaminoethanol, ethylenediamine, benzylamine, procaine, pyrrolidine, piperidine, morpholine, 1-ethyl piperidine, 2-piperidinoethanol and basic ion exchangers.

Por their intended uses the new compounds of Formula I, as well as thepharmaceutically acceptable salts of the acids of Formula I areadministered orally, rectally or parenterally preferably in form ofpharmaceutical compositions.

Pharmaceutical compositions according to the present invention contain,as active ingredient, at least one com pound of Formula I and /or apharmaceutically acceptable salt of an acid embraced by Formula I incombination with an inert carrier and, if desired, other additives. Theinven' tive compositions consist, preferably, of dosage unit forms whichare suitable for the oral, rectal or parenteral application of dailydoses of 1-80 mg./kg. of a compound of the invention for mammals.Suitable dosage unit forms for the oral or rectal application, likedrages, tablets, capsules, suppositories respectively, containpreferably 10 to 500 mg. of a compound of the invention.

In the above named dosage unit forms, the amount of active ingredient ispreferably between 5% and 90%. For preparation of tablets or dragecores, one combines the active ingredients for instance with solidpowder-like carriers such as lactose, saccharose, sorbitol or mannitol;starches such as potato starch, corn starch or amylopectin, highlydispersed silicon dioxide, additional laminaria powder or citrus pulppowder, cellulose derivatives or gelatine, if desired with the additionof lubricating agents like magnesium or calcium stearate or polyethyleneglycols and presses the mixture into the desired form.

The drage cores are coated, for instance, with concentrated sugarsolutions which can also contain arabic gum, talc and/or titaniumdioxide or with a light volatile organic solvent or solvent mixturewhich contains dissolved varnish. To these coatings can be addedpigments, for instance, to indicate different dosages of activesubstance. As other oral dosage unit forms, there are most suitableplugged capsules from gelatine and soft closed capsules from gelatineand a softening agent like glycerin. The first named contain the activeingredient, preferably as granulate, if desired in mixture with dilutingagents like corn starch, with lubricating agents, like talc or magnesiumstearate, and if desired, stabilisers, like sodium metabisulfite (Na S Oor ascorbic acid. In soft capsules the active ingredient is preferablydissolved or suspended in suitable fluids, such as liquid polyethyleneglycols, whereby, if desired, stabilisers can be added.

As dosage unit forms for the rectal application, are

suitable, for instance, suppositories which consist of a combination ofa compound of Formula I or a pharmaceutically acceptable salt of an acidembraced by Formult I, with a suppositorial ground mass, for instance,natural or synthetic triglycerides, or also gelatine rectal capsuleswhich contain a combination of the active ingredient with polyethyleneglycols.

Ampoule solutions for parenteral, especially intramuscular orintravenous administration contain, e.g. a compound of Formula I in aconcentration of preferably 0.5-5% as an aqueous dispersion preparedwith the aid of the usual dissolving agents and/or emulsifying agents aswell as, optionally, stabilisers, or they contain an aqueous solution ofa pharmaceutically acceptable, water soluble salt of a free acidembraced by Formula 1.

Other suitable dosage units for parenteral administration are, e.g.lotions, tinctures and ointments, prepared with the usual auxiliaryagents, for percutaneous application.

As mentioned above, the present invention relates also to methods ofalleviating pain and treating inflammatory diseases in mammals whichmethods comprise administering an effective amount of at least onecompound of the invention, preferably in form of an inventivepharmaceutical composition.

It is to be understood that the dosage administered will be dependent onthe species, the age, health and Weight of the recipient; the severityof the condition being treated; the kind of concurrent treatment, ifany; the frequency of treatment and the nature of the effect desired.Generally, the daily dosage of an active compound of Formula I will befrom about 1 to about mg./ kg. of bodyweight. A preferred range is fromabout 1 to about 60 mg./kg. of bodyweight per day.

The following examples will serve to further typify the nature of thepresent invention, but should not be construed as a limitation on thescope thereof.

Temperatures are given in degrees centigrade.

Example 1 58.0 g. of (p-nitrosophenyl)-acetic acid ethyl ester and 50ml. of butadiene are dissolved in 300 ml. of chloroform and the solutionis allowed to stand for 30' hours at 0. The reaction mixture is thenconcentrated by evaporation under 10 torr on a water-bath at 20. Theoily residue of 80 g. is crystallised from 550 ml. of petroleum ether(B.P. 50)/ether (3:2), by cooling of the solution to -25 during ca. 15hours. The [p-(3,6-dihydro-2H-l,2- oxazin-Z-yD-pheuyl] -acetic acidethyl ester, M.P. 3234, is obtained. A specimen distilled for theanalysis (B.P. 128-l30/0.1 torr), melts at 35-36", n =1.5448.

The ethyl ester required as starting material is produced as follows:

31.5 g. of (p-nitrophenyl)-acetic acid ethyl ester and 6.0 g. of calciumchloride are dissolved in 420 ml. of 99% ethanol and 150 ml. of water.The solution is heated, while stirring, to boiling and 50 g. of zincdust are introduced at this temperature within 10 minutes. The reactionmixture is then refiuxed for 15 minutes and filtered hot. The filtrateis washed twice with 75 ml. of ethanol each time. The filtrate andwashing liquid are mixed, still hot, together with 375 ml. of Water.

The obtained clear solution, which contains the(phydroxyamino-phenyl)-acetic acid ethyl ester, is rapidly cooled to 5and is then poured, while vigorously stirring, into a solution of g. ofiron(III)-chloro-hexahydrate in 375 ml. of water at room temperature. Agreen solution is formed, from which the (p-nitrosophenyl)- acetic acidethyl ester precipitates almost instantaneously in the form of yellowcrystals. After 5 minutes the crystals are filtered ofl, thoroughlywashed with water and dried for about 14 hours at 50. The(p-nitrosophenyD- acetic acid ethyl ester, M.P. 71-72, is obtained, andfrom this is obtained, by recrystallisation from Water] acetic acid, theanalytically pure substance, M.P. 72.

Example 2 15.5 g. of 2-(p-nitrosophenyl)butyric acid methyl ester and 19ml. of butadiene are dissolved in 75 ml. of chloroform and the solutionis allowed to stand for 17 hours at The reaction mixture is thenconcentrated by evaporation on a water-bath at 75 under 10 torr. Theaddition product remaining as a residue in crystalline form, M.P. 53-55(18.9 g., 96% of theoretical value) is crystallised from water-methanol(1:10) by cooling to 25 during 30 minutes, whereby 15.9 g. of2-[p-(3,6-dihydro- 2H-1,2-oxazin 2 yl)-phenyl]-butyric acid methyl esterM.P. 57-59, are obtained. A repeated recrystallisation of a specimenfrom water-methanol produces the analytically pure substance, M.P. 5960".

The methyl ester required as starting material is produced as follows:

(a) 41.8 g. of 2-(p-nitrophenyl)-butyric acid are refiuxed in a mixtureof 200 ml. of methanol and 5 ml. of concentrated sulphuric acid for 4hours. The reaction mixture is then intensively concentrated under 11torr, cooled to 0 and poured, while stirring, into ice water. The precipitated 2-(p-nitrophenyl)-butyric acid methyl ester is filtered off,washed with water and dried under 11 torr, M.P. 3335, yield 42.8 g.

(b) 33.5 g. of 2-(p-nitrophenyl)-butyric acid methyl ester and 48.0 g.of ammonium chloride are dissolved in 720 m1. of methanol and 225 ml. ofwater. 50 g. of zinc dust are added in small portions, while vigorouslystirring, within 20 minutes at room temperature and in a nitrogenatmosphere, whereby slight cooling is necessary. The reaction mixture isstirred for 15 minutes at room temperature and then it is poured througha filter with stirring at 0 into 53 ml. of 3 N hydrochloric acid. Thefiltrate is then washed with 80 ml. of methanol-water (1:3).

Filtrate and washing liquid, which contain the crude hydrochloride ofthe 2-(p-hydroxyamino-phenyl)-butyric acid methyl ester, are addeddropwise at 7 within 10 minutes, while stirring, to a solution of 90 g.of iron(III)- chloride-hexahydrate in 375 ml. of water at 5. Thesolution turns green and the 2-(p-nitrosophenyD-butyric acid methylester begins to precipitate immediately. After the addition iscompleted, the solution is stirred for a further 5 minutes at 5,whereupon the suspension is cooled to and filtered. The reactionproduct, which is filtered off, is washed with 30 ml. of water-methanol(1:1) and then with water. The crystals are dried for 15 hours at 30-40,whereby 21 g. of crude 2-(p-nitrosophenyl)-butyric acid methyl ester,M.P. 45-48" are obtained. By dissolving the product in 210 ml. ofmethanol at room temperature while stirring, filtering otf of the smallamount of undissolved substance and leaving the solution to stand during17 hours at 25, the 2-(p-nitrosophenyl)-butyric acid methyl ester, M.P.48-52, are obtained, which is sufiiciently pure for further processing.An analytically pure substance, M.P. 51-55", is obtained by furthercrystallisation from methanol.

Example 3 A solution of 37.1 g. of [p-(3,6-dihydro-2H-1,2-oxazin-2-yl)-phenyl]-acetic acid ethyl ester [cp.Example 1] in 900 ml. of ethanol and 700 ml. of water is added to asolution of 7.4 g. of sodium hydroxide in 200 ml. of water. The obtainedemulsion is stirred at room temperature, whereby a clear solution isobtained after ca. 3 minutes. After stirring for one hour, 0.1 Nhydrochloric acid is added until a pH value of 3.8 is obtained (ca. 1860ml.) and the mixture is extracted four times with ether(500+300-l-300-l-300 ml.). Each extract is washed with 100 ml. of water.The extracts are then combined, dried over magnesium sulphate andconcentrated by evaporation to dryness on a water-bath at 50 underreduced pressure, finally 10 torr. The crystalline residue of M.P.124-130 (with decomposition), consists of crude [p-3,6-dihydro-2H-1,2-oxazin-2-yl)-phenyl]-acetic acid (78% of theoreticalamount). By crystallisation from methanolwater (3:2) and then twice frombenzene, the pure substance, M.P. 134-135 (with decomposition) isobtained.

Example 4 2.61 g. of2-[p-(3,6-dihydro-2H-1,2-oxazin-2-yl)-phenyll-butyric acid methyl ester[cp. Example 2] are dissolved in 55 ml. of ethanol and 57 ml. of 0.39 Nsodium hydroxide solution and the solution is allowed to stand at roomtemperature for 24 hours. 0.18 N hydrochloric acid is then added toobtain a pH value of 2.2 (ca. 122 ml.). The obtained crystallineprecipitate is filtered 01f, washed with 10 ml. of ethanol-water (1:3)and then twice with water and dried for one hour under 1 torr at 50. The2-[p-(3,6-dihydro-2H-1,2-oxazin-2-yl)phenyl]- butyric acid, M.P. 112l14,is obtained. A specimen for analysis, which is recrystallised frommethanol-water (7:3), melts at 1l4115.

Example 5 43.0 g. of 2-(3chloro-4-nitroso-phenyl)-propionic acid methylester are added at -10 to a mixture of 48 ml. liquid butadiene and 190ml. chloroform and left to stand for 16 hours at 0. After evaporation ofthe solvent by reduced pressure, the crude 2-[3-chloro-4-(3,6-dihydro-2H-1,2-oxazin-2-yl)-phenyl]-propionic acid methyl ester is obtained as ared oil. This oil is purified in a bulb tube by distillation at140/0.001 torr. After crystallisation from ligroine, colourless crystalsare obtained with a melting point of 45-465".

The 2 (3 chloro 4 nitrosophenyl)-propionic acid methyl ester used asstarting material was prepared as follows:

(a) 101 g. methylmalonic acid diethyl ester was added dropwise withstirring over a period of 30 minutes at 2530 under nitrogen to asuspension of 13.9 g. of sodium hydride in 1300 ml. of dryN,N-dimethylformamide (DMF). The suspension was heated to and kept therefor about 1 hour. When evolution of hydrogen had ceased, the almostclear solution of sodium methylmalonic ester was cooled to roomtemperature. 129 g. of 2,4-dichloronitrobenzene was added in one portionand the resulting red solution heated at 95 for 3 hours. During heatingto 95 it was noticeable that the reaction was exothermic. The brown,turbid reaction mixture was evaporated to dryness from a Waterbath under10 mm. The oily residue was heated under reflux during 3 hours with 1160ml. of ethanol, 580 ml. of water, and 93 g. of sodium hydroxide pellets.900 ml. of water was added and the mixture distilled under 70 mm., untilthe distillation temperature was 50. About 2100 ml. of distillate wascollected. The ethanol-free residue was cooled to 20 and extracted withfive 250 ml. portions of ether. The aqueous phase was acidified to pH 2with 180 ml. of concentrated hydrochloric acid and the brown oil, whichseparated, extracted with two 500 ml. portions of ether. The combinedethereal extracts were washed with two 100 ml. portions of water toremove any DM'F, dried with magnesium sulphate, and evaporated todryness from a water bath (100) under 10 torr. The dark, oily residuewas heated under reflux during 4 hours with 525 ml. of methanol and 20ml. of concentrated sulphuric acid. The mixture was cooled to 10 andpoured on a mixture of 900 g. of ice water. The resulting emulsion Wasextracted with ether (600+ ml.), the ethereal solution was twiceextracted with 150 ml. of 20% of potassium hydrogen carbonate solutionand twice with 100 ml. of water, and dried with magnesium sulphate.Evaporation of the ether and distillation of the residue gave 2-(3-chloro-4-nitrophenyl)propionic acid methyl ester as an orange-yellowoil, I2 l25-140, 11 1.5448.

(b) 85 g. of 2 (3 chloro-4-nritro-phenyl)propionic acid methyl ester andM3 g. of ammonium chloride were dissolved in 1690 ml. of methanol and375 ml. of water. 116 g. of zinc powder were added in 5 g. portionsunder nitrogen over a period of 15 minutes at 2025 with stirring. Afteraddition was complete the mixture was stirred for another 15 minutes at2025, cooled to 10, and filtered with suction. The filtered solution wasadded with stirring to 117 ml. of 3 N hydrochloric acid cooled to 5 to10. The filter cake was washed with 250 ml. of water methanol of Theclear, light yellow filtrate (pl-I 1.5-2.0) containing the hydrochlorideof 2 (3- chloro 4 hydroxylamine-phenyl)-propionic acid methyl ester wasadded to a solution of iron(I'II) chloride [210 g. of iron(III) chloridehexahydrate in 685 ml. of water] with vigorous stirring at 0 to -5 overa period of 15 minutes. The green suspension was extracted three timeswith cold benzene (1500+500-l-500 ml.). The combined benzene extractswere washed at 0 with two 450 ml. portions of N hydrochloric acid, 400ml. of water, two 450 ml. portions of 20% potassium hydrogen carbonatesolution, and finally again two 400 ml. portions of water. The washedbenzene extract was dried with magnesium sulphate and evaporated todryness from a water bath (30) under torr. The2-(3-chloro-4-nitrosophenyl)-propionic acid methyl ester remains as agreen oil.

Example 6 45.6 g. of 2-[3-chloro-4-(3,6-dihydro-2H-1,2-oxazin-2-yl)-phenyl]-propionic acid methyl ester are stirred with a solution ofg. of sodium hydroxide in 100 ml. water and 200 ml. of methanol for anhour at 30. After acidification with 145 ml. of 3 -N hydrochloric acid,precipitates an oil. This oil is twice extracted with 500 ml. of etherand the whole ether extract is washed. with 100 ml. of Water, dried withmagnesium sulphide and concentrated by evaporation under reducedpressure. An oil is obtained which, after cooling, crystallisespartially. After recrystallisation of methanol Water, the 2-[3-chloro- 4(3,6 dihydro-ZH-1,2-oxazin-2-yl)-phenyl]-propionic acid is obtained,melting point 160-170".

The following prescriptions further illustrate the production of variousdosage units:

Example 7 1000 g. of active substance, e.g. [p-(3,6-dihydro-2H-1,2-oxazin-2-yl)-phenyl]-acetic acid, are mixed with 550 g. of lactoseand 292 g. of potato starch. The mixture is moistened with an alcoholicsolution of 8 g. of gelatine and is granulated through a sieve. Afterdrying, 60 g. of potato starch, 60 g. of talcum and 10 g. of magnesiumstearate and 20 g. of highly dispersed silicon dioxide are mixed in. Themixture is then pressed into 10, 000 tablets, each weighing 200 mg. andeach containing 100 mg. of active substance. Optionally, the tablets canbe provided with grooves for more accurate adjustment of the dosageamount.

Example 8 200 g. of active substance, e.g. [p-(3,6-dihydro2H-1,2-oxazin-2-yl)-phenyl]-acetic acid ethyl ester are mixed with 16 g. ofmaize starch and 6 g. of highly dispersed silicon dioxide. The mixtureis moistened with a solution of 2 g. of stearic acid, 6 g. of ethylcellulose and 6 g. of stearin in ca. 70 ml. of isopropyl alcohol and isgranu lated through a sieve III (Ph. Helv. V). The granulate is driedfor ca. 14 hours and is then pressed through sieve III-Illa. It is thenmixed with 16 g. of maize starch, 16 g. of talcum and 2 g. of magnesiumstearate and pressed into 1000 drage cores. These are coated with aconcentrated syrup of 2 g. of shellac, 7.5 g. of gum arabic, 0.15

g. of dyestufi, 2 g. of highly dispersed silicon dioxide, 25 g. oftalcum and 53.35 g. of sugar and dried. The obtained drages each weighs360 mg. and each contains 200 mg. of active substance.

Example 9 50.0 g. of 2 [3 chloro-4-(3,6-dihydro-2H-1,2-oxazin-2-yl)-phenyl]-propionic acid are dissolved in a mixture of 218 ml. of 1N sodium hydroxide solution and 500 ml. of boiled, pyrogen-free waterand, with water treated in the same manner, the solution is then made upto 2000 ml. The solution is filtered and used to fill 1000 ampoules eachcontaining 2 ml., and sterilised. A 2 ml. ampoule contains 50 mg. of2-[p-(1pyrryl)-phenyl]-butyric acid as active substance in the form ofthe sodium salt.

Example 10 50 g. of 2 [3-chloro-4-(3,6-dihydro-2H-1,2-oxazin-2-yl)-phenyl]-propionic acid and 1950 g. of finely ground suppositoryfoundation substance (e.g. cocoa butter) are thoroughly mixed and thenmelted. The melt is maintained homogeneous by stirring and from it aremade 1000 suppositories, each weighing 2 g. and each containing 50mg. ofactive substance.

Example 11 60.0 g. of polyoxyethylene-sorbitan monostearate, 30.0 g. ofsorbitan-monostearate, 150.0 g. of parafiin oil and 120.0 g. of stearylalcohol are melted together. 50.0 g. of[p-(3-dihydro-2H-1,2-oxazin-2-yl)-phenyl] -acetic acid (finelypulverised) are then added and 590 ml. of water, preheated to 40, areused to form an emulsion. The emulsion is stirred until it has cooled toroom temperature and is then poured into tubes.

What We claim is:

1. A pharmaceutical composition comprising an analgetically oranti-inflammatory effective amount of a compound of the formula QCMs...

wherein R is hydrogen, methyl or ethyl,

is hydrogen or halogen up to the atomic number 35, an

R is hydrogen, methyl or ethyl, or a pharmaceutically acceptable saltthereof, wherein R is hydrogen and a pharmaceutical carrier therefor.

2. The method of alleviating pain in a mammal comprising administeringto said mammal an analgetically elfective amount of a compound asdefined in claim 1, or a pharmaceutically acceptable salt thereof.

3. The method of treating inflammatory diseases in a mammal comprisingadministering to said mammal an anti-inflammatory efiective amount of acompound as defined in claim 1, or a pharmaceutically acceptable saltthereof.

References Cited UNITED STATES PATENTS STANLEY I. FRIEDMAN, PrimaryExaminer *zg gg e Ummo STATES ?ATENT' OFFICE I CERTTFECATE OF CORRECTION3:7 9:55? Dated Apli 1 Patent No.

ROLF DENSS ET AL Inventofls) It is certified that error appears in theabove-identified patent and that said Letters Patent are herebyeorrected as shown below:

Column 1, after line 12 and before line 13, insert Claims priority,applicationswitzerland April 29, 1968, 6375/68 Signed and sealed this1st day of October 1974.

. CSEALl Attest:

MCCOY M. GIBSON JR. (3. MARSHALL DANN Attesting Officer Commissioner ofPatents

